There is an urgent need for new approaches to treat and prevent HIV-associated cryptococcal meningitis (CM). Since CM occurs predominantly in the setting of impaired cell-mediated immunity, therapies and vaccines that enhance the immune response to C. neoformans are logical. Defined antibodies (Ab) to the cryptococcal capsular polysaccharide glucuronoxylomannan (GXM) enhance cellular immune responses to and are protective against C. neoformans. Although a vaccine that could elicit such Abs might have promise, polysaccharides are poorly immunogenic in HIV-infected (HIV+) individuals, and GXM elicits protective and non-protective Abs. In the previous funding period, our group isolated a peptide mimetic of GXM selected by a protective human MAb to GXM, and established proof of principle that a mimetic could serve as an immunological surrogate, or mimotope, for a GXM epitope. The mimotope, P13, was immunogenic and conferred protection against C. neoformans in normal and human immunoglobulin transgenic mice. Immune sera from immunized mice were protective in naive mice. There is concern that CD4+T cell deficiency may preclude immunization of HIV+ individuals against pathogens for which CD4+ T cells are essential for natural resistance to disease, such as C. neoformans. There is evidence that Abs to GXM regulate the cellular response to C. neoformans, and that cellular subsets other than CD4+ T cells contribute to host resistance to C. neoformans. This competing renewal application is designed to test the hypothesis that there may be plasticity in the cellular subsets that are required for vaccine- and Ab-mediated immunity to C. neoformans. The Specific Aims are: i) to determine the relationship between vaccine efficacy against C. neoformans and the immune status of the host; ii) to determine the relationship between vaccine efficacy against C. neoformans and the nature of the antibody response; and iii) to identify mechanisms of vaccine-induced antibody efficacy and the relationship of antibody efficacy to the immune status of the host. We will immunize normal mice and mice with T and B cell deficiency with the GXM peptide mimotope-conjugates produced in the past funding period to identify cellular subsets that are required or dispensable for vaccine- and Ab-mediated protection against C. neoformans. Naive and vaccine-elicited Abs from human immunoglobulin transgenic mice will be studied to allow us to characterize the nature of human Abs to GXM. The aims of this proposal will further our understanding of the determinants of vaccine and Ab efficacy against C. neoformans and provide proof of principle that vaccines can be developed that focus the immune response on cellular subsets that can induce protection: